The cognitive functions of the prefrontal cortex (PFC) are profoundly altered in mental illnesses such as schizophrenia, which are worsened by exposure to stress. Neuropathological studies have demonstrated loss of neuropil, including loss of dendritic spines, in the PFC of patients with schizophrenia, and imaging studies suggest that progressive loss of gray matter may be key to the deterioration in mental state. The proposed research examines a possible neurobiological basis for stress-induced changes in PFC cognitive function and structural integrity. Studies in animals have shown that the cognitive functioning of the PFC is impaired by exposure to either acute or chronic stress, and that chronic stress leads to dendritic spine loss in the PFC. The proposed research will examine the intracellular signaling mechanisms contributing to these marked changes in cognitive ability and dendritic integrity. We will test the hypothesis that activation of cAMP-HCN signaling (Hyperpolarization-activated Cyclic Nucleotide-gated cation channels) contributes to disconnections of PFC networks during stress exposure. This mechanism may have particular relevance to schizophrenia, as a loss-of-function mutation in DISC1 (Disrupted In Schizophrenia) likely leads to a disinhibition of cAMP signaling in PFC in many patients with this illness. We will specifically examine whether acute stress functionally disconnects PFC networks through cAMP opening of HCN channels, leading to rapid loss of PFC cognitive function. We will further examine whether chronic stress exposure leads to more profound cognitive impairment and actual loss of dendritic spines through sustained elevations in cAMP-HCN signaling. The research will examine these hypotheses using physiological, behavioral and anatomical assays of PFC integrity. Aim 1 will employ single-unit recordings of PFC neurons in monkeys performing a working memory task to observe the role of cAMP-HCN signaling in physiological measures of network connectivity (persistent firing during the delay period) under conditions that mimic the stress response. Aim 2 will determine whether cAMP-HCN signaling in PFC contributes to PFC cognitive deficits induced by acute stress exposure in rats. Aim 3 will use novel adenoviral techniques to test whether knockdown of HCN1 channels in rat PFC will protect PFC from the cognitive and architectural changes produced by chronic stress exposure. Positive results may lead to novel treatment strategies for neuroprotection of PFC grey matter in mental illness.